Certain women become hypertensive after chronic use of oral contraceptives. One estrogen metabolite, 2-hydroxyestrogen or catechol estrogen, is known to competitively inhibit the inactivation of catecholamines by catechol 0-methyltransferase. Since inhibition of the inactivation of catecholamines could potentiate or prolong the hypertensive effects of these hormones, we plan to explore the potential relationship between the catechol estrogen metabolite of synthetic estrogens and hypertension. We propose to study in rats the correlation between 1) contraceptive steroid induced changes in blood pressure, 2) in vivo catecholamine metabolism and 3) hepatic levels of catechol estrogen and the pattern of estrogen metabolism. Female rats will be treated chronically with low doses of either mestranol or a combination of ethynylestradiol and norethynodrel, both of which have been shown to have cardiovascular effects. The blood pressure response (magnitude and duration) to exogenously administered norepinephrine will be measured and correlated with blood catecholamine levels. The state of catecholamine metabolism will be assessed with (3H)-norepinephrine and include assay of methylated metabolites in the plasma and liver. Catechol estrogen levels in rat liver will be measured along with the extent of methylation of these products. The application of this approach to understanding individual susceptability to oral contraceptive toxicity will involve further study of the effects of several agents on the development of contraceptive steroid-induced hypertension. These agents, a) phenobarbital, b) thyroid hormone and c) Beta-naphthoflavone, each have distinct effects on the liver enzyme(s) which form catechol estrogens and are useful as modulators of the extent of in vivo estrogen metabolism. Study of these agents will help us to evaluate the extent to which catechol estrogen metabolites underlie certain risk factors, i.e. drug interactions, hyperthyroidism and cigarette smoking, for the development of estrogen-induced cardiovascular changes.